Lymphocyte specific kinase (Lck) is one of the first signaling molecules to be activated downstream of the T cell antigen Receptor (TCR). As a member of the Src-family of Tyrosine Kinases (TK), Lck shares their structural features with a unique NH2-terminal region, followed by Src-homoly (SH) domains SH3 and SH2, and a COOH-terminal TK domain. The SH domains allow Lck to directly bind not only with other protein complexes, but also display intramolecular interactions that stabilize the conformation and modulate the Lck enzymatic function. The exquisite fine-tuned regulation of Lck activity underscores the importance of this protein in T cell activation. In this context, Lck is critical for thymocyte development, lnterleukin-2 (IL-2) production and homeostatic proliferation of T cells. Indeed, aberrant Lck activity has been associated with a broad spectrum of T cell-derived pathologies, including autoimmune diseases (AD). Our laboratory has been dissecting the molecular mechanisms underlying the spontaneous systemic AD of mice that are deficient in the expression of the T cell Specific Adapter (TSAd) protein. We have shown that TCR-induced production of IL-2 is impaired in primary T cells from TSAd-/- mice, which may account for the development of the AD in these mice. Furthermore, we have recently demonstrated that TCR/CD28-induced activation of Lck is defective in TSAd-/- T lymphocytes. We postulate that the impaired Lck activity is the primary cause of the development of the autoimmune disease in TSAd-/- mice. In this regard, we propose to explore the mechanism by which TSAd regulates Lck activity and understand the consequences of aberrant Lck regulation in TSAd-/- T cells. Specifically, in Aim 1 we will test the hypothesis that TSAd binds directly to Lck and we will reveal the structural and functional features of this interaction. In Aim 2 we will unravel the signaling events differentially modulated in TSAd-/- T lymphocytes as a result of the reduced Lck activity. It is anticipated that these studies will lead a new line of research focused on novel means by which Lck is regulated with the ultimate goal to define alternative therapeutic approaches to the treatment of AD. [unreadable] [unreadable] [unreadable]